Genetic Variant CARS1:p.Leu285Phe (chr11-3029392-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001014437.3(CARS1):c.853C>T(p.Leu285Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,614,076 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 77 hom. )

Consequence

CARS1
NM_001014437.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.911

Publications

12 publications found

Variant links:

Genes affected

CARS1 (HGNC:1493): (cysteinyl-tRNA synthetase 1) This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2010]

CARS1 links:

CARS1-AS1 (HGNC:40125): (CARS1 antisense RNA 1)

CARS1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010881454).

BP6

Variant 11-3029392-G-A is Benign according to our data. Variant chr11-3029392-G-A is described in ClinVar as Benign. ClinVar VariationId is 731546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00778 (1185/152350) while in subpopulation AMR AF = 0.0101 (154/15302). AF 95% confidence interval is 0.00936. There are 10 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARS1	NM_001014437.3	MANE Select	c.853C>T	p.Leu285Phe	missense	Exon 8 of 23	NP_001014437.1	P49589-3
CARS1	NM_001194997.2		c.853C>T	p.Leu285Phe	missense	Exon 8 of 23	NP_001181926.1
CARS1	NM_001751.6		c.604C>T	p.Leu202Phe	missense	Exon 7 of 22	NP_001742.1	P49589-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARS1	ENST00000380525.9	TSL:1 MANE Select	c.853C>T	p.Leu285Phe	missense	Exon 8 of 23	ENSP00000369897.4	P49589-3
CARS1	ENST00000397111.9	TSL:1	c.604C>T	p.Leu202Phe	missense	Exon 7 of 22	ENSP00000380300.5	P49589-1
CARS1	ENST00000278224.13	TSL:1	c.604C>T	p.Leu202Phe	missense	Exon 7 of 22	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes

AF:

0.00778

AC:

1185

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00998

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00758

AC:

1906

AN:

251400

AF XY:

0.00769

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00928

GnomAD4 exome

AF:

0.00945

AC:

13808

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00923

AC XY:

6709

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33480

American (AMR)

AF:

0.00358

AC:

160

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00853

AC:

223

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00117

AC:

101

AN:

86258

European-Finnish (FIN)

AF:

0.0177

AC:

943

AN:

53374

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0106

AC:

11802

AN:

1111904

Other (OTH)

AF:

0.00888

AC:

536

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

678

1356

2035

2713

3391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00778

AC:

1185

AN:

152350

Hom.:

Cov.:

AF XY:

0.00862

AC XY:

642

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41578

American (AMR)

AF:

0.0101

AC:

154

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0216

AC:

230

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00998

AC:

679

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00832

Hom.:

Bravo

AF:

0.00641

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00780

AC:

947

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00932

EpiControl

AF:

0.00759

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.54

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.069

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.040

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.16

PhyloP100

0.91

PrimateAI

Benign

0.28

PROVEAN

Benign

0.53

REVEL

Benign

0.12

Sift

Benign

0.74

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.16

MVP

0.21

MPC

0.26

ClinPred

0.0012

GERP RS

-3.0

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.018

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over